6: Hypersensitivities

Allergenic potential of Drugs

Dependent on their chemical properties, Increases in molecular size and complexity

What drugs account for 80% of allergic or pseudoallergic reactions to drugs?

β-lactam antibiotics, aspirin, NSAIDS, sulfonamides

What determines allergy: innate or adaptive immune system?

While the innate immune system plays a critical role in both phases of allergy, the dependence of clinical symptoms on the ADAPTIVE arm of the immune system is what constitutes allergy

Sensitization

Exposure to agent that renders interaction with immune cells is required to induce allergic sensitization, vary in potency, exposure route required to induce sensitization, etc., Usually, no clinical signs

Elicitation

Subsequent encounters with allergen, Result in clinical signs/symptoms

Gell and Coomb's Classification of Hypersensitivity Reactions

Type I, Type II, Type III, Type IV

What is type I hypersensitivity also called?

Antigen-specific, IgE-mediated allergic reactions

Type I Common Reactions

Dermal: Atopic dermatitis, Contact urticaria; Respiratory: Allergic rhinitis, Allergic asthma; Some food allergies; Systemic: Anaphylaxis

How do Type I hypersensitivities occur?

1. Allergen exposure 2. Allergen processing by antigen presenting cell 3. Antigen processing & travel to lymph node 4. Presentation to naive T-cells 5. T-cell helper 2 differentiation stimulation fo B-cell/isotype switching 6. Plasma cell travels back to mucosa, memory cells circulate, allergen-specific IgE production 7. Binding to mast cell receptors 8. At the second time of exposure, basophil/mast cell activation/degranulation 9. Histamine, Prostaglandin D2, Leukotrienes B4, C4, D4, Platelet activation factor, Cytokines/chemokines 10. Bronchoconstriction, vasodialtion, itchy eyes, skin, nose, throat, wheel and flare

How fast do Type I Hypersensitivities occur?

"Immediate" reaction, 15 minutes-1 hour onset, Most urgent of adverse reactions, Early and late phase reactions

How can you diagnose type I hypersensitivity?

Diagnosis- prick testing, "Atopic" individuals (part of the population are having higher levels of IgE but the cause is unknown)

What drugs cause type I hypersensitivity?

Penicillins, Cephalosporins, Neuromuscular-blocking agents, Vancomycin

Percutaneous (Prick) Skin testing

(Positive control: Histamine) A drop for each test material is placed on the volar surface of the forearm, Prick the skin with a sharp needle inserted through the drop at 45 Degree angle. Interpret the skin response after 15 min. If the prick is nonreactive, intradermal test. (Used for dust, pollen allergies)

Intradermal test

Inject intradermal (enough to produce small bleb), Wait 15 min, Ate last 3 mm greater than negative control (Used for penicillin allergy)

Blood tests

(Immunoassays) Enzyme-linked immunosorbent assay (ELISA), Radioallergo-sorbent test (RAST), Will detect specific IgE against specific antigens (food proteins, dust...)

What can happen if a patient is taking antihistamines before a prick skin test?

Could cause false-negative reactions

Pros of skin prick

Fast, Less expensive

Cons of skin prick

Itchiness after prick, High training, Drug interference, Patients could go through anaphylaxis (not often)

When is blood test used instead of skin prick?

Medication interference (corticosteroids, anti-histamines), Eczema or psoriasis, Strong allergen (extreme response), Babies

Blood test (ELISA) for Hypersensitivity Type I

Allergens coat, chromogenic enzyme binds to IgE indicating positive test result

Atopy

The hereditary trait of producing excessive levels of IgE antibodies, therefore predisposing to type I hypersensitivity

How do Type II & III hypersensitivities occur (sensitization only)?

1. Antigen exposure 2. Antigen processing by antigen presenting cell 3. Antigen processing & travel to lymph node 4. Presentation to naive T-cell 5. T-cell Helpers 2 differentiation stimulation of B-cell/isotype switching 6. Plasma cell travels back to mucosa, memory cells circulate, allergen-specific IgM and IgG production

How do Type II hypersensitivities occur (elicitation only)?

1. Antigen exposure second time 2. Binding by IgG or IgM 3. Recruitment of Macrophages or NK Cells/Classical activation of complement cascade 4. Cell death

What are Type II Hypersensitivity reactions also called?

Cytotoxic reactions

Type II Hypersensitivity

Cytotoxic reactions mediated by tissue-specific IgG or IgM, Directed towards cell surface antigens or haptens bound to cell surface, Very often involve blood: Hemolytic anemia (Transfusion reactions and Erythroblastosis fetalis), Thrombocytopenia; Goodpasture's syndrome- collagen Abs

Type II Hypersensitivity Medications

Penicillins, Heparin, Sulfonamides

Direct Coombs Test

Looking for patient's ANTIGEN (in this case, the antigens from the red blood cells and identify blood type)

Indirect Coombs Test

Looking for patient's ANTIBODIES against a particular antigen, (in this case, looking if a patient has developed antibodies against blood type from previous exposure)

Indirect Coombs Test: Looking for patient's ANTIBODIES against a particular antigen, (in this case, looking if a patient has developed antibodies against blood type from previous exposure)

ELISA Antibody Titer

To determine antibody titer, a positive specimen is serially diluted 5-fold or more and then tested on the ELISA. The endpoint titer is determined by the last diluted specimen that gives positive results on the ELISA. Antibody titer indicates the level of the antibodies in a blood sample, defined as the greatest dilution (lowest concentration) of the blood sample at which an antibody assay, such as ELISA, still produces a detectable positive result. The higher the antibody concentration in the blood, the greater the dilution that will produce a detectable signal.

Erythroblastosis Fetalis

Hemolytic anemia in the fetus (breaking down of rbc) Caused by incompatible Rh types of the mother and fetus (mother being Rh- and fetus being Rh+) Fetal erythrocyte Rh stimulates mother Ab production. Generally, only an issue after the sensitizing pregnancy by first child being Rh+ sensitization (exposure), and second child also being Rh+ > (elicitation: reaction to the second child)

Allo-immunization (Allo-antibodies)

Immunologic reaction against foreign antigens that are distinct from antigens on an individual's cells.

Auto-antibodies

Immunologic reaction against own's antigens present on an an individual's cells.

RhoGAM Injection

IgG anti-RhD, After delivery of a Rh-positive baby within 72h of birth, Routine prevention of Rh immunization at 26-28 weeks of pregnancy, Maternal or fetal bleeding during pregnancy, Pregnancy lost at or up to 12 weeks of pregnancy, Ectopic pregnancy

When can RhoGAM be used outside pregnancy?

Can also be used when a Rh (-) patient receives Rh (+) blood or blood products

Pregnancy + ABO Incompatibility

Not always severe, Bilirubinemia and jaundice may occur due to hemolytic disease Treatment: phototherapy to aid bilirubin degradation or and exchange blood transfusion (replace blood)

Type III Hypersensitivity

IgM or IgG/antigen complexes accumulate in tissues or circulation, triggering inflammation, Arthrus reaction, Can also occur following high doses of inhaled allergens induce IgG responses, over IgE (Farmer's lung)

Type III Hypersensitivity Medications

Minocyclin, Quinidine, Penicillins

How do Type III hypersensitivities occur (elicitation only)?

1. Antigen exposure second time 2. Bound by antibody 3. Deposition into basement membrane of blood vessels 4. Activation of complement 5. Recruitment of inflammatory cells, additional damage 6. Inflammation

Is Type II Hypersensitivity a complex?

Antibody + cell surface-bound antigen = NOT a complex; Clinical symptoms correspond to tissue of antibody attachment and cell destruction

Is Type III Hypersensitivity a complex?

Antibody + soluble antigen = immune complex; Clinical symptoms correspond to deposition location of immune-complexes

Type IV Hypersensitivity (Skin)

Allergic contact dermatitis (ACD), Metal allergy, poison ivy, Stevens-Johnson Syndrome (SJS) , Toxic Epidermal Necrolysis (TEN), Mosquito "bites", Mantoux test (TB)

Type IV Hypersensitivity (Lungs)

Chronic beryllium disease, Tuberculosis, Hypersensitivity pneumonitis

Type IV Hypersensitivity (Misc)

Celiac disease and type I diabetes (allergic response + autoimmune component)

How do Type IV hypersensitivities occur?

1. Allergen passes through stratum corneum and interacts with APCs 2. Hapten-carrier complex formation 3. Antigen uptake, processing, travel to lymph nodes, presentation to naive T-cell 4. Travel to the skin 5. IFN-y production increases vascular adhesion molecules activates macrophages stimulate keratinocytes 6. neutrophil & monocyte influx 7. Antigen/tissue destruction

SJS

< 10% body surface area

TEN

> 30% body surface area

SJS and TEN

Similar in pathology- differ in degree of distribution, Severe mucocutaneous eruptions 7-21 days after initiation of drug: Varicella zoster vaccine, Sulfonamides, penicillins, antiepileptics, abacavir, carbamazepine, NSAIDS, acetaminophen

How fast does SJS and TENS occur?

Often presents in the skin, but responses can become systemic, "Delayed" onset, 1-3 days after re-exposure

How can you diagnose TENS/SJS?

Patch testing, Athymic individuals do not develop Type IV disorders

Can you take antihistamine when doing Intradermal (late reading) or patch for SJS?

In this case, patient can take antihistamine since type IV is mediated through T-cells

Irritants

NOT hypersensitivity reactions, Exposure to irritants may produce similar signs as hypersensitivity, ACD-like rash on the skin, Asthmatic-like response on the lungs, Non-specific inflammatory response, No adaptive immune component, Usually strong/oxidizing/corrosive chemicals

Irritants: Drugs

Pulmonary irritants, Desflurane, other inhalation anesthetics, Dermal irritation can be a side effect of many drugs, Topical application, Maybe not drug itself, but constituent of formulation, Careful with prolonged exposure- patches

Pseudo-allergies

The agent itself will activate effector pathways involved in true allergies but without the induction of Ig: Complement will get activated without the need of IgG or IgM binding to the antigen (CARPA) - COMPLEMENT ACTIVATION-RELATED PSEUDOALLERGY Mast cells will degranulate and release histamine without IgE, Prostaglandin synthesis will also be affected.

How do Pseudo-allergies differ from Type I hypersensitivity?

It mimics symptoms of the hypersensitivity type I, but complement is also involved

What drugs are associated with pseudo-allergic reactions?

Opiates, Vancomycin, ACEI, Radiocontrast agent, PEG (Polyethylene glycol)

What is special about doses for pseudoallergic reactions?

Dose-dependent, It can occur first time exposed to the agent, since there is no need for sensitization

Challenge with PEG if used as liposomes for drug delivery

Repeated administration of PEG can cause an Accelerated Blood Clearance (ABC) phenomenon > antibodies are going to recognize faster the liposomes > phagocytosis > content of the liposome will be degraded before being released.

Type I

IgE-Mediated, Systemic anaphylaxis, Hay fever, Asthma , Food allergies, Eczema

Type II

IgG/M-Mediated, Cytotoxicity, Blood transfusion reactions, Autoimmune, hemolytic anemia

Type III

Immune Complex-Mediated, Serum sickness, Systemic lupus erythematosus, Rheumatoid arthritis

Type IV

Cell-Mediated (Th1, Th2, CD8+), Contact dermatitis, Tubercular lesions, Graft rejection, SJS/TEN

CD4: What does Th1 Release?

IFN-y

CD4: What does Th2 Release?

IL-4, IL-5